The Gm and Am allotypes are known to be codominant genetic markers coded for by a series of closely-linked autosomal genes. There is probably a single constant region gene for each of the IgG and IgA subclasses, and approximately 27 Gm and 1 Am markers, and a tentative IgM marker. Some have been shown to correlate with single or dual amino acid substitutions in the C region. Despite more than 18 years of study since the first Gm marker was defined, as yet no definitive chromosomal assignment has been made for genes coding for C regions of human immunoglobulins. The purpose of the present proposal is to pursue chromosomal assignment and linkage analysis for the Gm and Am markers and to pursue linkage regarding the various C regions in the human for which genetic markers have not as yet been defined. Basically, two approaches will be employed: 1) The study of human lymphoblast -mouse (fibroblast, lymphoblast, or hepatoma) cell hybrids with an attempt to achieve chromosomal assignment for differentiated functions of B cells, in particular surface receptors, secreted immunoglobulins, aggregate receptor and EAC receptor sites. Attempted linkage analysis for these differentiated B-cell functions will be made, and linkage with the 1- antitrypsin (Pi) locus will be sought. The effect of mitogens and immunogens (e.g. dextran) known to elicit restricted Ig synthesis will be studied. 2) The detailed study of patients with variable immunodeficiency syndromes of the type previously shown to relate to structural or regulatory gene defects will be continued. Although this group of patients represents only about 20-25 per cent of patients with variable immunodeficiency, the intensive study of this group and their families is particularly relevant to the understanding of the interrelationships in synthesis occurring among the various Ig classes, IgG subclasses and Gm genetic markers. This analysis requires radioimmunoassay of minor classes and subclasses which may not be detected by conventional radial diffusion techniques. By fully defining the missing C region gene product in this unusual group of patients and in family members we can begin to define those genes which may either be concomitantly deleted and hence more closely linked or under conjoint regulatory control.